1. By: Salma Sadek Hefzi Group 4 Presented to: Dr. Nashaat Lotfy

2. Camptothecin analogues They are plant alkaloids derived from the Asian "Happy tree"(camptotheca acuminata) They are cell cycle specific chemotherapeutic agents acting on the S-phase(phase of DNA synthesis) They are Irinotecan(CAMPTOSAR® Pfizer) and Topotecan(Hycamtin® GSK)

3. Mechanism of action: Both drugs inhibit the action of topoisomerase I (an enzyme that produces reversible single-strand breaks in DNA during DNA replication. These single-strand breaks relieve torsional strain and allow DNA replication to proceed). Camptothecin analogues bind to the topoisomerase I- DNA complex and prevent religation of the DNA strand, resulting in double-strand DNA breakage and cell death.

4. Mechanism of resistance: 1) Decreased expression of Topoisomerase I. 2) Mutations in Topoisomerase I enzyme with decreased binding affinity to drug. 3) Increased expression of multi drug-resistant phenotype with over expression of P170 glycoprotein (enhanced efflux and decreased intracellular accumulation) 4) In Irinotecan the decreased formation of the active metabolite SN-38(through dec. activity and/or expression of carboxylesterase enzyme)

5. Structures: IRINOTECAN TOPOTECAN

6. Indications: IRINOTECAN TOPOTECAN 1) Metastatic colorectal cancer in combination with 5-FU and leucovorine. 2) Metastatic colorectal cancer as monotherapy when treatment containing 5-FU has failed. 3) Small cell lung cancer(in combination with cisplatin) 4) Non-small cell lung cancer. 1) Metastatic ovarian cancer when first line therapy has failed. 2) Small cell lung cancer (as single agent) 3) Cervical cancer with cisplatin

7. Pharmacokinetics: IRINOTECAN TOPOTECAN A--> Not given by oral route D-->Widely distributed in body tissues. -PB: Irinotecan: 30-60% SN-38: 95% M-->Converted to active metabolite SN-38 by carboxyl esterase enzyme primarily in liver and also in plasma and intestinal mucosa. -Further metabolism of SN-38 occurs in liver. E--> Major route is in bile and feces. A--> rapidly absorbed from oral route. D-->Widely distributed in body tissues. PB:10-53% M-->In plasma: Rapid conversion of Topotecan in plasma and aqueous soln. from the lactone ring form to the carboxylate form. -At PH 4 lactone ring form predominates while at physiologic PH the carboxylate form predominates. In liver: Minimal and mediated by CYP450 E-->40-60% renally excreted

8. Dosage range: IRINOTECAN TOPOTECAN There are several recommendations: 1) Starting dose of 125 mg/m 2 IV weekly for 4 weeks followed by 2 weeks rest. It can be modified to 2 weeks and 1 week rest (USA) 2) 300-350 mg/m 2 IV every 3 weeks. (Europe). 3) 180 mg/m 2 IV as monotherapy or in combination with infusional 5-FU/LV on every 2 weeks schedule. Usual dose is 15 mg/m 2 IV for 5 consecutive days given every 21 days.

9. Administration: IRINOTECAN TOPOTECAN Administered IV usually over 90 min. continuous infusion. Administered IV over 30 min. or by 24 hr. continuous infusion. For combination therapy with Cisplatin, administer pretreatment hydration. For oral administration: taken with or without food. If vomiting occurs after dose, don’t take replacement dose.

10. Stability: IRINOTECAN TOPOTECAN Store intact vials at RT and protect from light. Doses should be diluted in 250- 500 ml D 5 W or NS to a final conc. Of 0.12-2.8 mg/ml. (It appears to be more stable in D 5 W than NS due to the relatively acidic pH) Soln. in D 5 W are stable for 24 hrs. at RT or 48 hrs. under refrigeration. Soln. diluted in NS may ppt. if refrigerated. Don’t freeze. IV: store intact vials of lyophilized powder at RT and protect from light. Reconstitute with 4 ml SWFI This soln. is stable for up to 28 days at RT. It should be further diluted in 50-100 ml D 5 W or NS This soln. is stable for 24 hrs. at RT or up to 7 days under refrigeration.

11. Side effects: IRINOTECAN TOPOTECAN 1)Myelosuppression (typical nadir occurs at days 7-10 with complete recovery by days 21- 28) 2)Diarrhea 3)Mild alopecia 4)Nausea and vomiting. 5)Chills, fatigue, fever, sweating and weight loss. 1)Myelosuppression 2)Nausea and vomiting in 60- 80% of patients. 3)Headache, fever, malaise, arthralgias and myalgias. 4)Microscopic hematuria. 5)Alopecia

12. Drug interactions: IRINOTECAN 1-CYP3A4 enzyme stimulants: increase rate of metabolism or Irinotecan and SN-38 (phenytoin, carbamazepine, Rifampin and st. john's worts) 2-CYP3A4 enzyme inhibitors: decrease rate of metabolism of the drug and thus increase its level and potential toxicity.(Ketoconazole, itraconazole, clarithromycin, erythromycin) 3-Diuretics may increase dehydration due vomiting and diarrhea. 4-Chronic use of dexamethasone may inc. drug clearance. 5-Avoid concurrent use with etoposide due to potential hepatotoxicity.

13. Common protocols: IRINOTECAN TOPOTECAN Metastatic colorectal cancer: IFL Douillard(6 weeks cycle) FOLFIRI(2 week cycle) For all regimens, the dose of LV should be administered immediately after CAMPTOSAR, with the administration of 5-FU to occur immediately after receipt of LV. Small cell lung cancer: Irinotecan+Cisplain Cervical cancer Topotecan+cisplatin Cisplatin: 50 mg/m 2 IV on day 1 Topotecan: 0.75 mg/m 2 /day IV on days 1-3

14. Special considerations: I) IRINOTECAN: ManagementClinical pictureProblem Patients should routinely receive anti-emetic prophylaxis with 5HT3 receptor antagonists(ondansetron,gra nisetron)in combination with dexamethasone. 1)Emetogenic atropine(0.25-1 mg) administered IV unless clinically contraindicated. Routine atropine prophylaxis is not recommended unless a previous cholinergic event has been experienced. Diarrhea, diaphoresis, abdominal cramps during infusion or within 24 hrs. of drug administration(may be due to cholinergic effect) 2)Early diarrhea syndrome

15. ManagementClinical pictureProblem Loperamide should be taken immediately after the first loose bowel movement (4 mg PO as loading dose then 2 mg every 2 hrs. around the clock and 4 mg every 4 hrs. at night) Discontinue when patient is free for 12 hrs. Starts after 24 hrs. of drug administration and can lead to severe dehydration and/or electrolyte imbalance if not adequately managed. 3)Late diarrhea an oral flouroquinolone should be added. If diarrhea continued without improvement for 24 hrs. hospitalization with IV antibiotics and IV hydration should be considered. If still resistant

16. ManagementClinical pictureProblem Flush with sterile water, elevate extremity and local application of ice. Site of infusion should be inspected for extravasation 4)Moderate vesicant Dose reduction should be considered in this setting. Increased risk of developing myelosuppression and GI toxicity. 5)Patients with UGT1A1 7/7 genotype 6) Irinotecan should be held for grade 3 and/or grade 4 diarrhea. Dose of drug should be reduced upon recovery. 7) Patients should be warned against taking laxatives during therapy. 8) Use with caution in patients >65 years, patients with poor performance status and in those previously treated with pelvic and/or abdominal irradiation as they are at increased risk of myelosuppression and diarrhea. 9) Pregnancy category D and breast feeding should be avoided.

17. Special considerations: II)TOPOTECAN 1)Use with caution in patients with abnormal renal function and it requires dose reduction(baseline CrCl is critical with frequent monitoring) 2)Monitor CBC on weekly basis. 3)Mild vesicant 4)If granulocyte nadir count is low, begin G-CSF(Neupogen®) or GM-CSF(Sargramostim) 24 hrs. after completion of Topotecan therapy. 5) Pregnancy category D and breast feeding should be avoided. 6)Shouldn’t be given to patients with neutrophil count 100,000/mm 3 7)For oral form, retreatment Hgb should be > 9 g/dl

18. Oral Topotecan GlaxoSmithKline announced approval by the FDA for oral Hycamtin ® (topotecan) capsules for the treatment of relapsed small cell lung cancer (SCLC). Specifically, Hycamtin capsules are indicated for patients who had a complete or partial response to first-line chemotherapy and who are at least 45 days from the end of that treatment. Hycamtin capsules are the only oral single- agent chemotherapy approved for the treatment of SCLC after failure of first-line therapy. Hycamtin Also studies showed that oral HYCAMTIN showed equal efficacy to docetaxel in relapsed NSCLC.